Expression of ADAMTS-4 by chondrocytes in the surface zone of human osteoarthritic cartilage is regulated by epigenetic DNA de-methylation.
The two major aggrecanases involved in osteoarthritis (OA) are ADAMTS-4 and ADAMTS-5. Knock-out studies suggested that ADAMTS-5, but not ADAMTS-4, is the major aggrecanase in murine OA. However, studies of human articular cartilage suggest that ADAMTS-4 also contributes to aggrecan degradation in human OA. This study investigated ADAMTS-4 in human OA. While ADAMTS-4 was virtually absent in control cartilage, numerous ADAMTS-4 immuno-positive chondrocytes were present in OA cartilage and their numbers increased with disease severity. RT-PCR confirmed expression, especially in the surface zone. DNA methylation was lost at specific CpG sites in the ADAMTS-4 promoter in OA chondrocytes, suggesting that the increased gene expression was more than a simple up-regulation, but involved loss of DNA methylation at specific CpG sites, resulting in a heritable and permanent expression of ADAMTS-4 in OA chondrocytes. These results suggest that ADAMTS-4 is epigenetically regulated and plays a role in aggrecan degradation in human OA.
Cheung
Kelvin S C
KS
Bone and Joint Research Group, IDS Building, MP887, General Hospital, University of Southampton, Southampton, UK. karatekelvin@gmail.com
Hashimoto
Ko
K
Yamada
Norikazu
N
Roach
Helmtrud I
HI
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000071121:ADAMTS4 Protein; D000368:Aged; D000369:Aged, 80 and over; D002358:Cartilage, Articular / Q000378:metabolism*; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism*; D011348:Procollagen N-Endopeptidase / Q000235:genetics / Q000378:metabolism*
D051722:ADAM Proteins; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human